Stent for liberating drug

ABSTRACT

A stent according to the present invention is adapted to be introduced into a vascular system such as blood vessels. The stent includes a stent body produced by weaving or knitting a fiber containing a drug and made of a low-melting biodegradable polymer into a tubular shape, or coating a drug-containing low-melting biodegradable polymer on a stent body. When the stent is introduced into the vascular system, the drug contained therein is dosed in a locally limited region of the vascular system. The low-melting biodegradable polymer used has a melting point of 80° C. or lower and is at least one compound selected from the group consisting of poly-ε-caprolactone, poly-D, L-deca-lactone, poly-dioxane and a copolymer thereof.

TECHNICAL FIELD

This invention relates to a stent for liberating a drug which isintroduced into a vascular system such as blood vessels, and moreparticularly to a stent used for a local dosage of the drug.

BACKGROUND ART

For instance, in angioplasties, vascular walls are likely to be damagedby insertion of a catheter such as a balloon catheter or anatheroma-resecting catheter thereinto so that there occurs proliferationof the tunica intima due to a healing reaction in the vascular walls,which frequently results in a so-called restenosis.

Such restenosis is caused by a hyperplasia of smooth muscle cells and amajority of the recurrence of the disease is ascertained by anangiography, for example, 3 months after the angioplasty operation.

The frequency of the restenosis sums to about 30 to 40% though it variesdepending upon facilities used in the angioplasty operation. If anyrestenosis does not occur 3 months after the operation, it is suggestedthat the restenosis is no longer caused subsequently.

Meanwhile, any method for preventing the aforementioned restenosis hasnot yet been established. However, attempts, which have been made forthis purpose until now, include methods in which an instrument such as astent or an atheroma-resecting catheter is used, or other methods towhich genetic engineering is applied or in which drugs such as anantimetabolite, e.g., a carcinostatic agent, a fibroblasthyperplasia-preventing agent, or the like are used.

However, in the event that the catheter, for example, theatheroma-resecting catheter, is used to prevent the restenosis of bloodvessels, patients suffer from significant pain and such an operation canbe repeated only in a limited manner.

In addition, introduction of the stent into a portion subjected to theangioplasty provides some effect to prevent obliteration of bloodvessels. However, since the stent itself has no function for restrictinghyperplasia of smooth muscle cells and preventing the restenosis, theessential problem still remains unsolved. Moreover, upon theintroduction of the stent into a portion subjected to the angioplasty,there is a possibility that thrombus will occur. Under thesecircumstances, in the event that the stent is used, in order to preventoccurrence of such thrombus, there has been proposed a method in whichdosage of an antithrombotic agent such as dextran, aspirin, warfarin, orthe like is used.

On the other hand, it is considered that dosage of drugs capable ofrestricting hyperplasia of smooth muscle cells is effective to preventrestenosis without use of instruments such as the stent, because suchdosed drugs can function so as to prevent restenosis itself. However, inthis case, some problems have been posed with respect to the dosagemethod of these drugs.

Similarly, in the event that the stent is used together with theantithrombotic agent to prevent thrombus, some problems have been alsoposed on the dosage of the antithrombotic agent.

In consequence, a locally limited dosage is regarded as an effectivemethod for dosage of the drugs capable of restricting hyperplasia ofsmooth muscle cells or the antithrombotic agent. The locally limiteddosage is carried out by a method in which a so-called dispatch catheteris used, a method in which a sweat balloon catheter is used, a method inwhich a double balloon catheter is used, a method in which the drugs areselectively introduced through a catheter, or the like.

The dispatch catheter is composed of a non-porous polyurethane sheathand a spiral coil wound around the polyurethane sheath. Drugs to bedosed are supplied into the spiral coil so that the drugs can be broughtinto contact with walls of blood vessels. The sweat balloon cathetercontains a balloon having a microporous structure. When such a sweatballoon catheter is used, drugs are gradually dosed through fine poresof the balloon into an interior of the blood vessels. The double ballooncatheter contains two balloons by which opposite ends of the portionsubjected to the angioplasty are closed such that drugs are introducedthrough the catheter into a portion of the blood vessel between theseballoons.

The aforementioned locally limited dosage methods can advantageouslyincrease the concentration of the drug to be dosed, because the dosageof the drug is carried out in the locally limited region. To thecontrary, since it is necessary to continuously retain the catheter inthe blood vessel and thereby block a bloodstream, the locally limiteddosage has such a disadvantage that it cannot be used over a long periodof time. For instance, in the event that the sweat balloon catheter orthe double balloon catheter is used, the locally limited dosage must becarried out within several minutes. Whereas, even in the event that thedispatch catheter is used or the drug is selectively introduced throughthe catheter, the time required for the dosage of the drug is limited toseveral hours. In addition, these methods have a further problem in thatthey can be carried out only in an operating room.

Moreover, it is known that a whole-body dosage is made by a peroral,transcutaneous or transluminal dosage of drugs so that the drugs arecirculated through the whole body and reaches aimed cells. Thewhole-body dosage has an advantage in that it can be used over a longperiod of time.

However, in case of the whole-body dosage, the concentration of the drugin the blood is undesirably raised so that there is a possibility thatunexpected side effects such as hepatopathy, an aspiration accident, anexcess or failed dosage will occur. In addition, when an antithromboticagent is dosed by the whole-body dosage method, fine arteries and veinsin a brain are damaged so that an intracerebral hemorrhage is likely tooccur. Moreover, in case where a long-term dosage is made, a largeamount of drug is dosed such that a huge medical expense is required.

As described above, although many attempts have been made to preventrestenosis, for example, after an angioplasty operation, any effectivemethod which makes the locally limited and long-term dosage of drugspossible, has not yet been found until now.

DISCLOSURE OF THE INVENTION

The present invention has been accomplished to overcome theaforementioned problems. It is therefore an object of the presentinvention to provide a novel stent for liberating or eluting a drug,which is capable of a locally limited and long-term dosage of the drug.

As a result of long-term intense investigations and studies made by thepresent inventors, the stent has been developed based on a novelconcept.

That is, in accordance with the present invention, there is provided astent which is adapted to be introduced into a vascular system such asblood vessels. The stent is composed of a stent body formed by weavingor knitting a fiber, which contains a drug and is made of abiodegradable polymer having a low-melting point at whichpharmacological effects of the drug are not damaged, into a tubularbody.

In this case, the amount of the drug to be added to the biodegradablepolymer is determined depending upon the kind of drug thereof. When theamount of the drug in the biodegradable polymer is too small, the drugreleased into the vascular system decreases so that an effect by thedosage of the drugs cannot be exhibited to a sufficient extent. On theother hand, when the amount of the drugs in the biodegradable polymer istoo large, the healing process in walls of blood vessels is completelyrestricted so that formation of fibers or coats becomes difficult.

The kind of drug added may be selected according to the symptom or theaimed use. Examples of such drugs may include an antimetabolite such asa carcinostatic, a fibroblast hyperplasia-preventing agent, anantithrombotic agent or the like.

The drugs as a solute are dissolved in the biodegradable polymer as asolvent to form a solution. The solution is then hardened into a fiberfrom which the stent is prepared. Alternatively, the solution may becoated on a rigid stent body having an adequate mechanical strength, forexample, a metal stent body or a tubular woven or knitted stent bodymade of a biodegradable polymer having a high melting point.

In this case, when heated to an elevated temperature, the drug issusceptible to undesired change in its molecular structure, which leadsto loss of the aimed effect or conversion to a toxic substance.

In general, the biodegradable polymer used as sutures, for example,poly-lactic acid or poly-glycolic acid, has a melting point ranging fromabout 220° C. to about 240° C. Consequently, there might occur aninconvenience that the drugs added thereto is subjected to undesiredchemical conversion, when heated to such elevated temperature.

Accordingly, it is required that the biodegradable polymer have a lowmeting point at which the drug added can be present without loss of thepharmacological effects. For example, it is desirable to have themelting point of the biodegradable polymer at 80° C. or lower.

Examples of suitable low-melting biodegradable polymers may includepoly-ε-caprolactone, poly-D, L-deca-lactone, poly-di-oxanone or acopolymer of these compounds, which have a melting point of about 63° C.

However, the aforementioned low-melting biodegradable polymers cannotnecessarily exhibit sufficient mechanical strength. In consequence, itis suitable that the fiber composed of the low melting biodegradablepolymer containing the drug be woven or knitted together with those madeof a high-melting biodegradable polymer to form the tubular stent body.

On the other hand, the drug added may include an antimetabolite such asa carcinostatic, a fibroblast hyperplasia-preventing agent, or the like.For the purpose of preventing restenosis, TRANIRAST is the preferreddrug.

TRANIRAST is an oral anti-allergic agent and widely used as remedies forbronchial asthma, allergic thiniris or atopic dermatitis. It has beenrecently found that TRANIRAST has an effect of restricting a hyperplasiaof smooth muscle cells. As a result, the drug is expected to show apreventive effect against the restenosis. Actually, the presentinventors have confirmed preventive effect of TRANIRAST againstrestenosis.

The stent according to the present invention is adapted to be introducedinto a vascular system and retained in a particular region of thevascular system. At this time, the drug contained in the biodegradablepolymer is released or eluted into the vascular system over 3 months inassociation with biodegradation of the stent. As a result, the drugcontained in the biodegradable polymer is allowed to be continuouslydosed into a locally limited region of the vascular system over a longperiod of time while maintaining its concentration in a constant level.

In this case, such a locally limited dosage of the drug can be carriedout without any risk of causing adverse side effects as observed in thecase of the whole-body dosage. In addition, this makes it possible todose a relatively small amount of the drugs over a long period of time.

Moreover, differing from the conventional locally limited dosage, thepresent invention can provide a long-term dosage without inflictingserious pain on a patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view schematically showing one embodiment of astent according to the present invention.

FIG. 2 is a perspective view schematically showing essential parts oftwo folded yarn composed of a fiber made of a high-melting biodegradablepolymer and a fiber containing a drug and made of a low-meltingbiodegradable polymer.

FIG. 3 is a perspective view schematically showing another embodiment ofa stent according to the present invention.

FIG. 4 is a perspective view showing the condition in which the fibercontaining the drug and made of a low-melting biodegradable polymer isplaced around a stunt body formed from a high-melting biodegradablepolymer fibers and then melted so as to adhere to an outer surfacethereof.

FIG. 5 is a perspective view showing a high-melting biodegradablepolymer fiber which is knitted into a stent body of a stent according toa further embodiment of the present invention.

FIG. 6 is a perspective view showing the condition in which the fibershown in FIG. 5 is coated with a solution composed of the low-meltingbiodegradable polymer containing the drug.

FIG. 7 is a perspective view showing a stent formed by knitting thehigh-melting biodegradable fiber which is coated with the solutioncomposed of the low-melting biodegradable polymer containing the drug.

FIG. 8 is a perspective view showing a stent body formed from the fibercomposed of the high-melting biodegradable polymer.

FIG. 9 is a perspective view showing a still further embodiment of astent according to the present invention in which the stent body shownin FIG. 8 is coated with the drug-containing low-melting biodegradablepolymer solution.

FIG. 10 is a perspective view showing a still further embodiment of astent according to the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail by way ofspecific examples by referring to the accompanying drawings.

EXAMPLE 1

The present Example shows one example of a stent which is effective forpreventing a restenosis after an angioplasty operation. In Example 1, adrug used there is TRANIRAST (N-(3, 4-dimethoxy-cinnamoyl)-anthranilicacid) represented by the following chemical formula: ##STR1##

TRANIRAST is one of the fibroblast hyperplasia-preventing agents. Tamaiet at., one of the inventors of the present application, reported thatclinical experiments in which TRANIRAST was continuously dosed for 3months at a dosage amount of 600 mg per day (one tablet after everymeal), surprisingly showed a restenosis rate of 15% or lower.Consequently, the drug has been expected to provide a remarkablepreventive effect against restenosis.

TRANIRAST was added to and dissolved in a biodegradable polymer composedof poly-ε-caprolactone having a melting point of about 63° C. to preparea polymer solution.

The thus-prepared polymer solution was a mixture containing TRANIRAST inan amount of 1 to 2% by weight based on poly-ε-caprolactone.

The polymer solution was then subjected to a spinning process to preparea fiber composed of a TRANIRAST-containing poly-ε-caprolactone.

Next, as shown in FIG. 1, the fiber composed of a TRANIRAST-containingpoly-ε-caprolactone was knitted into a tubular shape to form a stentbody 10. End portions of the fiber constituting the stent body weretreated to obtain a stent 11.

The thus-obtained stent 11 was produced by knitting thepoly-ε-caprolactone fiber 1 having a diameter of about 0.05 mm and alength of 90 cm into a tubular shape having a diameter of 3 mm and alength of 20 mm.

EXAMPLE 2

The present Example shows another example of a stent which is producedby knitting a drug-containing low-melting biodegradable polymer fiberand a high-melting biodegradable polymer fiber together.

In Example 2, as the drug-containing biodegradable polymer fiber, therewas used the TRANIRAST-containing poly-ε-caprolactone fiber 1 preparedin the same manner as described in Example 1 above. The fiber wasprepared in a similar manner to that of Example 1 by subjecting thepolymer solution containing 1 to 2% by weight of TRANIRAST based onpoly-ε-caprolactone to a spinning process.

The TRANIRAST-containing poly-ε-caprolactone fiber 1 and thehigh-melting biodegradable polymer fiber 2 was formed into a two foldedyarn 3 as shown in FIG. 2. The two folded yarn 3 was knitted into astent body 10 to obtain a stent 11.

In this case, the high-melting biodegradable polymer fiber 2constituting the two folded yarn 3 was produced by subjectingpoly-lactic acid or poly-glycolic acid to a spinning process.

In addition, the TRANIRAST-containing poly-ε-caprolactone fiber 1constituting the two folded yarn 3 was a spun yarn having a diameter ofabout 0.05 mm. The high-melting biodegradable polymer fiber 2 was also aspun yarn having a diameter of about 0.05 mm. The stent body 10 wasproduced by knitting the two folded yarn having a length of 90 cm to atubular body having a diameter of 3 mm and a length of 20 mm.

The size of the stent body 10 may be varied properly depending upon thevascular system to which the stent was applied.

Alternatively, the stent 11 can be formed by first knitting the stentbody 10 and then coating the low-melting biodegradable polymer solutioncomposed of a mixture of a solvent and a drug on the stent body 10, sothat the amount of the drug contained in the stent can be controlledproperly. In this case, as the low-melting biodegradable polymersolution, there is suitably used a mixture solution prepared by mixing70 cc of acetone, 1 g of TRANIRAST and 1 g of poly-ε-caprolactonetogether. In the event that the solution is coated, it is desirable thatthe stent body 10 is subjected to a heat treatment to evaporate acetoneas the solvent component.

In the foregoing, the two folded yarn 3 composed of theTRANIRAST-containing poly-ε-caprolactone fiber 1 and the high-meltingbiodegradable polymer fiber 2 was used to obtain the knitted stent body10. However, a composite twisted yarn composed of pluralTRANIRAST-containing poly-ε-caprolactone fibers 1 and plural thehigh-melting biodegradable polymer fibers 2 may be used for the purpose.

EXAMPLE 3

In this Example, a high-melting biodegradable polymer fiber 2 waspreliminarily knitted into a tubular shape to prepare a stent body 30.The TRANIRAST-containing poly-ε-caprolactone fiber 1 as thedrug-containing low-melting biodegradable polymer fiber was wound aroundthe stent body 30 in an interlocking relation to each other so as toform a stent 21, as shown in FIG. 3. The fiber 1 was also produced bysubjecting the polymer solution containing 1 to 2% by weight ofTRANIRAST based on poly-ε-caprolactone to a spinning process.

In addition, the high-melting biodegradable polymer fiber 2 used in thisExample was also a poly-lactic acid fiber, a polyglycolic acid polymerfiber or a fiber composed of a copolymer thereof.

In this Example, the stent body 30 may be also coated with a polymersolution prepared by mixing 1 g of TRANIRAST as a drug and 1 g ofpoly-ε-caprolactone with 70 cc of acetone, so that the amount ofTRANIRAST to be contained in the stent 20 can be controlled properly.

EXAMPLE 4

In this Example, using the same procedure as described in Example 3above, the high-melting biodegradable polymer fiber 2 was preliminarilyknitted into a tubular shape to form the stent body 30. TheTRANIRAST-containing poly-ε-caprolactone fiber 1 as the drug-containinglow-melting Biodegradable polymer fiber was then wound around an outercircumferential surface of the stent body 30 in an interlocking relationto each other so as to form a stent 21, as shown in FIG. 3. Thethus-prepared stent 20 was heated by a heating means 35 as shown in FIG.4 to smoothen an outer surface of the stent. The heating means 35 usablehere may be a blower capable of blowing hot air.

Specifically, the stent 21 was heated to a temperature at which theTRANIRAST-containing poly-ε-caprolactone fiber 1 was not completelymolten, namely up to the melting point of poly-ε-caprolactone or atemperature lower than the melting point, whereby an outer peripheralsurface of the TRANIRAST-containing poly-ε-caprolactone fiber 1 wascaused to melt so that the outer surface of the stent 21 was smoothened.

The TRANIRAST-containing poly-ε-caprolactone fiber 1 may be alsoproduced by subjecting the polymer solution containing 1 to 2% by weightof TRANIRAST based on poly-ε-caprolactone to a spinning process. Inaddition of the high-melting biodegradable polymer fiber 2 may be also apoly-lactic acid fiber, a polyglycolic acid polymer fiber or a fibercomposed of a copolymer thereof.

The smoothened outer surface of the stent 21 permits a smooth insertionof the stent into a vascular system such as blood vessels.

EXAMPLE 5

In this Example, a high-melting biodegradable polymer fiber 42 wascoated with a solution of a drug-containing low-melting biodegradablepolymer and then the coated fiber was knitted into a stent 41.

In the production of the stent 41, a biodegradable polymer materialhaving a melting point higher than that of the drug-containinglow-melting biodegradable polymer was subjected to a spinning process toobtain the biodegradable polymer fiber 42 as shown in FIG. 5. At thistime, the high-melting biodegradable polymer fiber 42 used here may befiber prepared by subjecting poly-lactic acid, poly-glycolic acid or acopolymer thereof to a spinning process.

The biodegradable polymer fiber 42 was coated with a solution 43 ofdrug-containing low-melting biodegradable polymer as shown in FIG. 6.The solution 43 of drug-containing low-melting biodegradable polymerused here was a solution prepared by mixing 1 g of TRANIRAST as a drugand 1 g of poly-ε-caprolactone with 70 cc of acetone as a solvent.

Next, the high-melting biodegradable polymer fiber 42 on which thedrug-containing low-melting biodegradable polymer solution 43 wascoated, was knitted to form the stent 41.

Successively, the thus-knitted stent 40 was heated to evaporate acetone.The stent 40 was preferably heated to a temperature at which thedrug-containing low-melting biodegradable polymer 43 was stillmaintained in an unmolten state. This was because melting of thedrug-containing low-melting biodegradable polymer 43 was to be preventedupon heating.

Meanwhile, in the event that acetone as a solvent was already evaporatedduring production of the knitted stent body 40, the heating step can beomitted.

Thereafter, the stent body 40 from which acetone as a solvent wasevaporated, was formed into the stent 41, as shown in FIG. 7, bytreating end portions of the fiber 42 constituting the stent body 40.

In addition, the knitted stent body 40 may be further coated with thelow-melting biodegradable polymer solution 43 prepared by mixing 1 g ofTRANIRAST as a drug and 1 g of poly-ε-caprolactone with 70 cc of acetoneso that the amount of TRANIRAST as a drug coated on the stent body 40,can be adjusted to a proper level. In this case, it is preferred thatthe stent body is heated to evaporate acetone as a solvent.

EXAMPLE 6

In the aforementioned Examples, the high-melting biodegradable polymerfiber was first coated with the solution of the drug-containinglow-melting biodegradable polymer and then the fiber was knitted to formthe stent. On the other hand, in this Example, the high-meltingbiodegradable polymer fiber 42 prepared by subjecting poly-lactic acid,poly-glycolic acid or a copolymer thereof to a spinning process wasfirst knitted into a stent boy 50 as shown in FIG. 8. Applied over thestent body 50 was a low-melting biodegradable polymer solution 53containing a drug as shown in FIG. 9 to form a stent 51 of this Example.

The drug-containing low-melting biodegradable polymer solution 53applied to the stent body 50 was a polymer solution containing 1 to 2%by weight of TRANIRAST based on poly-ε-caprolactone in the solution.

The application of the low-melting biodegradable polymer solution 53 tothe stent body 50 may be carried out by coating the solution 53 over anouter circumferential surface thereof. Alternatively, the low-meltingbiodegradable polymer solution 53 may be applied to the stent body 50 byimmersing the stent body 50 therein.

EXAMPLE 7

This Example shows a further example of a stent which is produced bycoating a drug-containing biodegradable polymer solution over a stentbody.

In this Example, a stent 61 was produced by coating the drug-containingbiodegradable polymer solution on the stent body made of metal to form alayer 62 composed of drug-containing biodegradable polymer over an outersurface of the stent body 60, as shown in FIG. 10. The solution coatedcontained 1 to 2% by weight of the drug based on poly-ε-caprolactone(having a melting point of 63° C.) in the solution.

The stent body 60 used above was made of a metal material having athickness of 0.05 mm to 0.1 mm and formed into a cylindrical body havinga diameter of 2.5 mm to 4 mm and a length of 15 mm to 25 mm. Examples ofthe metal material may include stainless steel, tantalum or the like.

The stent prepared in each of the aforementioned Examples was introducedinto the blood vessel after angioplasty operation and held in place. Asa result, it was confirmed that dosage of TRANIRAST was carried out inan adequate manner for a long period of time, whereby occurrence of therestenosis was considerably reduced.

INDUSTRIAL APPLICABILITY

As is apparently understood from the aforementioned detaileddescription, the use of the stent according to the present inventionenables a continuous, locally limited and long-term dosage of the drug.

In addition, such a dosage can prevent occurrence of side effects sothat pains inflicted on patients can be minimized.

What is claimed is:
 1. A stent for liberating TRANIRAST, which isadapted to be introduced into a vascular system such as blood vessels,comprising a stent body produced by weaving or knitting into a tubularshape a fiber containing TRANIRAST and made of a low-meltingbiodegradable polymer having a melting point at which no pharmacologicaleffects of TRANIRAST are damaged.
 2. A stent for eluting TRANIRASTcontained therein, comprising a stent body coated with a mixturecomposed of TRANIRAST and a low-melting biodegradable polymer having amelting point at which no pharmacological effects of TRANIRAST aredamaged.
 3. A stent for liberating a drug, which is adapted to beintroduced into a vascular system such as blood vessels, comprising:astent body produced by weaving or knitting into a tubular shape acomposite fiber composed of fiber made of a low-melting biodegradablepolymer having a melting point at which no pharmacological effects ofthe druq are damaged and a fiber made of a high-melting biodegradablepolymer having a melting point higher than that of the fiber composed ofthe low-melting biodegradable polymer;wherein the low-meltingbiodegradable polymer exposed to an outer surface of the stent body isheat-fused to smoothen the outer surface; wherein the high-meltingbiodegradable polymer is at least compound selected from the groupconsisting of poly-lactic acid, polyglycolic acid and a copolymerthereof; wherein the melting point of the low-melting pointbiodegradable polymer is 80° C. or lower; and wherein the compositefiber constituting the stent body is a two folded yarn, the two foldedyarn including a TRANIRAST-containing poly-ε-caprolactone fiber.